Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease

Aslan, Mutay; Ryan, Thomas M.; Adler, Brian K.; Townes, Tim M.; Parks, Dale A.; Thompson, J. Anthony; Tousson, Albert; Gladwin, Mark T.; Patel, Rakesh P.; Tarpey, Margaret M.; Batinić‐Haberle, Ines; White, C. Roger; Freeman, Bruce Α.

doi:10.1073/pnas.221292098

Cited by 349 publications

(357 citation statements)

References 65 publications

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“…Although NY1DD mice do not exhibit hemolysis, BERK mice show more than 2-fold increase in cell-free plasma heme compared with controls [16] that may result in consumption/ inactivation of NO by ferrous hemoglobin as described [35]. In addition, transient vasoocclusive events in BERK mice, caused by intravascular sickling, will result in reperfusion injury and oxidant generation contributing to NO consumption by O 2 •− [3,16]. Thus, arginine supplementation is likely to enhance NO production and reduce oxidative stress in models of hemolysis and reperfusion injury [4,6,24].…”

Section: Protective Effect Of Argininementioning

confidence: 95%

“…The concept that sickle cell disease (SCD) is a state of inflammation has been substantiated by the reports of endothelial injury/activation and excessive generation of ROS in this disease, and enhanced leukocyte-endothelium interactions [3,13,15,31]. The oxidative stress in SCD is likely the result of intravascular sickling and transient vaso-occlusive events.…”

Section: Introductionmentioning

confidence: 99%

“…In SCD, growing evidence shows reduced bioavailability of nitric oxide (NO), probably due to consumption of NO by free oxygen radicals, and/or by cell free-plasma heme as a result of hemolysis [3,35]. In SCD and sickle mouse models, a preponderance of recent observations shows depleted levels of L-arginine, a substrate for NO, and NO metabolites (NOx) [24,25,36].…”

Section: Introductionmentioning

confidence: 99%

“…However, there is no definitive data on the status of antioxidant enzyme and lipid peroxidation according to the disease severity, as well as on the effect of NO replenishment. Among the likely sources of O 2 •− in SCD are plasma membrane NADPH oxidase [12,44], enzyme NO synthase due to depleted substrate arginine [40] and increased plasma xanthine oxidase (XO) activity [3,41].…”

Section: Introductionmentioning

confidence: 99%

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Protective effect of arginine on oxidative stress in transgenic sickle mouse models

Dasgupta

Hebbel

Kaul

2006

Free Radical Biology and Medicine

129

101

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Sickle cell disease (SCD) is characterized by reperfusion injury and chronic oxidative stress. Oxidative stress and hemolysis in SCD result in inactivation of nitric oxide (NO) and depleted arginine levels. We hypothesized that augmenting NO production by arginine supplementation will reduce oxidative stress in SCD. To this end, we measured the effect of arginine (5% in mouse chow) on NO metabolites (NOx), lipid peroxidation (LPO) and selected antioxidants in transgenic sickle mouse models. Untreated transgenic sickle (NY1DD) mice (expressing ~75% β S -globin of all β-globins; mild pathology) and knockout sickle (BERK) mice (expressing exclusively hemoglobin S; severe pathology) showed reduced NOx levels and significant increases in the liver LPO compared with C57BL mice, with BERK mice showing maximal LPO increase in accordance with the disease severity. This was accompanied by reduced activity of antioxidants (glutathione [GSH], total superoxide dismutase [SOD], catalase and glutathione peroxidase [GPx]). However, GSH levels in BERK were higher than in NY1DD mice indicating a protective response to greater oxidative stress. Importantly, dietary arginine significantly increased NOx levels, reduced LPO and increased antioxidants in both sickle mouse models. In contrast, L-NAME, a potent non-selective NOS inhibitor, worsened the oxidative stress in NY1DD mice. Thus, attenuating effect of arginine on oxidative stress in SCD mice suggests its potential application in the management of this disease.

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Section: Protective Effect Of Argininementioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Protective effect of arginine on oxidative stress in transgenic sickle mouse models

Dasgupta

Hebbel

Kaul

2006

Free Radical Biology and Medicine

129

101

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“…This can also result from the excessive superoxide derived from either activated leukocytes [31] or the abnormal deposits of xanthine oxidase [32] or the increased vascular wall myeloperoxidase [33] seen in the sickle context. Two other potential causes of deficient eNOS activity have not (yet) been supported by data in the sickle context: deficiency of eNOS enzyme amount and abnormal eNOS activity related to abnormal enzyme phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Endothelial nitric oxide synthase and nitric oxide regulate endothelial tissue factor expression in vivo in the sickle transgenic mouse

et al. 2009

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Activation of the coagulation system is a characteristic feature of sickle cell anemia, which also includes clinical thrombosis. The sickle transgenic mouse abnormally expresses tissue factor (TF) on the pulmonary vein endothelium. Knowing that this aberrancy is stimulated by inflammation, we sought to determine whether nitric oxide (NO) contributes to regulation of endothelial TF expression in the sickle mouse model. We used the NY1DD sickle mouse, which exhibits a low-TF to high-TF phenotype switch on exposure to hypoxia/reoxygenation. Manipulations of NO biology, such as breathing NO or addition of arginine or L-NAME (N-nitro-L-arginine-methyl-ester) to the diet, caused significant modulations of TF expression. This was also seen in hBERK1 sickle mice, which have a different genetic background and already have high-TF even at ambient air. Study of NY1DD animals bred to overexpress endothelial nitric oxide synthase (eNOS; eNOSTg) or to have an eNOS knockout state (one eNOS 2/2 animal and several eNOS 1/2 animals) demonstrated that eNOS modulates endothelial TF expression in vivo by down-regulating it. Thus, the biodeficiency of NO characteristic of patients with sickle cell anemia may heighten risk for activation of the coagulation system. Am. J. Hematol. 85:41-45, 2010. V

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Nitric Oxide for Inhalation in the Acute Treatment of Sickle Cell Pain Crisis

Gladwin¹

2011

JAMA

207

139

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Context Inhaled nitric oxide (NO) has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC). Objective To determine whether inhaled NO gas reduces the duration of painful crisis in patients with SCD who present to the emergency room or hospital for care. Design, Setting and Participants Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled NO gas versus inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004 and December 22, 2008. The primary endpoint was the time to resolution of painful crisis, defined by: 1) freedom from parenteral opioid use for 5 hours; 2) pain relief as assessed by visual analog pain scale scores ≤ 6 cm; 3) ability to walk; and 4) patient and family’s decision, with physician consensus, that the remaining pain could be managed at home. Intervention Inhaled NO gas versus inhaled nitrogen placebo. Results There was no significant change in the primary endpoint between the NO and the placebo groups, with a median time to resolution of crisis of 73.0 hours (95% CI: 46.0–91.0) and 65.5 hours (95% CI: 48.1–84.0), respectively (P=.87). There were no significant differences in secondary outcome measures, including length of hospitalization, VAS scores, cumulative opioid usage and the rate of acute chest syndrome. Inhaled NO was well tolerated with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed compliance and randomization, but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite. Conclusions Among patients with SCD hospitalized with VOC, the use of inhaled NO compared with placebo did not improve time to crisis resolution.

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Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease

Cited by 349 publications

References 65 publications

Protective effect of arginine on oxidative stress in transgenic sickle mouse models

Protective effect of arginine on oxidative stress in transgenic sickle mouse models

Endothelial nitric oxide synthase and nitric oxide regulate endothelial tissue factor expression in vivo in the sickle transgenic mouse

Nitric Oxide for Inhalation in the Acute Treatment of Sickle Cell Pain Crisis

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